Pain originating from visceral organs such as stomach or intestine is an alarm of pathology, for example, pain associated with inflammatory bowel diseases, including Crohn's disease and ulcerative colitis. Despite recent advances in the treatment of colitis using systemic or local anti-inflammatory therapies, many patients still complain of intractable visceral pain. In a rat model of colitis, we propose to reverse signs of nociception at behavioral and neuronal levels by blocking novel cellular and molecular targets in the central nervous system. We hypothesize that, in rats with experimental colitis, immunogenic microglial cells in the spinal cord become activated and release pro-inflammatory mediators, which then enhance the excitability of visceral sensory neurons, leading to nociceptive behavior. We further hypothesize that activated microglia, but not other cell types of the spinal cord, selectively express the stress-activated protein p38 and adenosine triphosphate receptor P2X4, whereas blocking these signaling pathways attenuates neuronal hyperexcitability and behavioral signs of visceral nociception. These studies will help us begin to define sites for pharmacologic interventions that are remote (within the spinal cord) and distinct from the organ of initial pathology (the colon) to improve the analgesic potency of biologic therapies, while minimizing undesirable side effects. PUBLIC HEALTH RELEVANCE: Inflammation or injury to a visceral organ (an 'internal'organ like stomach or gut) is often associated with unpleasant visceral sensation of pain. Certain forms of visceral pain, such as that induced by colon inflammation, cannot be effectively managed. To ameliorate treatment options for intractable visceral pain, we show in this application preliminary evidence for successful reversal of pain behavior in rats with colitis by blocking novel cellular and molecular targets in the spinal cord. Unique features of our proposal include the remote location of these targets from the site of colon inflammation, the multidisciplinary approach, and the diversified expertise of our team of investigators.